Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Recent epidemiological studies revealed that obesity results in a substantial increase in cancer risk including HCC. Accordingly, it was described that obesity promotes liver inflammation and tumorigenesis in mice by enhancing circulating levels of inflammatory cytokines such as IL-6 and TNF. Therefore, in obesity associated cancers an ideal molecular target is the one whose inhibition should a) suppress cancer cell proliferation, and b) reduce body adiposity and circulating inflammatory cytokines. Id1 (inhibitor of DNA binding 1) is a helix-loop-helix (HLH) transcription factor that functions as a negative regulator f basic helix-loop-helix (bHLH) transcription factors. Id1 promotes cell proliferation and inhibits cellular differentiation. It was shown that Id1 is overexpressed in many human cancers including HCC, however, the specific role of Id1 in HCC initiation and progression is not known. Recently, I discovered that Id1 is highly expressed in adipose tissues, especially in brown adipose tissue (BAT), and Id1-deficiency in mice resulted in enhanced thermogenesis due to induced expression of PGC1 and UCP1, critical regulators of thermogenesis. These studies together suggest that Id1 functions as a critical regulator in two different cellular processes; cell proliferation and cellular metabolism. Taken together, I hypothesize that deletion of Id1 suppresses obesity associated HCC by two mechanisms: 1. Id1 is required for cancer cell proliferation, and deletion of Id1 suppresses liver tumor growth. 2. Deletion of Id1 enhances thermogenesis, reduces body adiposity and circulating inflammatory cytokines, therefore, prevents liver inflammation that contributes to liver tumor growth. The objective of this proposal is to investigate the specific role of Id1 in obesity associated liver tumorigenesis. In pursuit of this two specific aims are proposed. Aim 1: I will investigate the consequence of loss of Id1 in the regulation of PGC1 and UCP1 in BAT mediated thermogenesis. For this purpose, I generated Id1fl/fl conditional knockout mice and adipose tissue specific deletion of Id1 will be achieved by crossing with aP2Cre mice which will allow me to investigate the impact of loss of Id1 in the regulation of thermogenic pathway and body adiposity. Aim 2: The second aim will investigate the effect of loss and overexpression of Id1 in liver tumorigenesis, and identify potential cooperating partners of Id1 that are involved in HCC progression. For this purpose I will use Id1fl/flAlbCre mice, and generate a new transgenic model (Alb- Id1Tg) to evaluate the consequence of liver specific loss and overexpression of Id1 on HCC initiation and progression. In addition, by combined deletion of Id1 in adipose tissue and liver, and by utilizing high fat die (HFD) model of obesity, I will investigate if lack of Id1 prevents obesity associated HCC.